NOVEL CHEMICAL COMPOUNDS HAVING PDE-IV INHIBITION ACTIVITY

Abstract: Novel purine derivatives and their isoguanine and dithioxanthine precursor compounds are disclosed. These compounds have bronchial and tracheal relaxation and/or anti-inflammatory activity. The invention is also related to processes for their preparation, to pharmaceutical compositions containing them and to their medical use. In certain preferred embodiments, the invention relates to 3-substituted and 3,8-disubstituted 6-amino purine derivatives.

Description: NOVEL CHEMICAL COMPOUNDS HAVING PDE-IV INHIBITION ACTIVITY BACKGROUND OF THE INVENTION The present invention relates to purine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use. In particular the invention relates to 3-substituted and 3,8- disubstituted 6-amino purine derivatives having bronchial and tracheal relaxation and/ or anti-inflammatory activity. The invention is also related to the isoguanine and dithio- xanthine precursor compounds of these purine derivatives, to pharmaceutical compositions containing them and to their medical use. Cyclic nucleotide phosphodiesterases (PDEs) have received considerable attention as molecular targets for anti-asthmatic agents. Cyclic 3' ,5'-adenosine monophos¬ phate (cAMP) and cyclic 3' ,5•-guanosine monophosphate (cGMP) are known second messengers that mediate the functional responses of cells to a multitude of hormones, neurotransmitters and autocoids. At least two therapeu- tically important effects could result from phosphodi- esterase inhibition, and the consequent rise in intra- cellular adenosine 3 ',5•-monophosphate (cAMP) or guanosine 3',5 • -monophosphate (cGMP)in key cells in the pathophysi- ology of asthma. These are smooth muscle relaxation (re¬ sulting in bronchodilation) and anti-inflammatory activity. It has become known that there are multiple, distinct PDE isoenzymes which differ in their cellular distribution. A variety of inhibitors possessing a marked degree of selectivity for one isoenzyme or the other have been synthesized. The structure-activity relationships (SAR) of isozy e- selective inhibitors has been discussed in detail, e.g., in the article of Theodore J. Torphy, et al., "Novel Phospho- diesterases Inhibitors For The Therapy Of Asthma", Drug News & Prospectives, 6(4) May 1993, pages 203-214. The PDE enzymes can be grouped into five families according to their gpecificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. PDE I is stimulated by Ca 2+ /calmodulin. pDE ιτ ± s C GMP-stimu- lated, and is found in the heart and adrenals. PDE III is cGMP-inhibited, and possesses positive inotropic activity. PDE IV is cAMP specific, and possesses airway relaxation, antiinflammatory and antidepressant activity. PDE V appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE V inhibitors may have cardiovascular activity. While there are compounds derived from numerous struc¬ ture activity relationship studies which provide PDE III inhibition, the number of structural classes of PDE IV inhibitors is relatively limited. It has previously been shown that the 3,8-disubsti- tuted 6-thioxanthine derivatives as described in EP-A- 0256692 exhibit enhanced bronchodilator and anti-inflam a- tory activity compared to the corresponding xanthine de¬ rivatives. Transformation of these 6-thioxanthine deriva¬ tives to the corresponding isoguanines substantially re¬ duces the bronchodilator and anti-inflammatory activity. PDE IV (and possibly PDE V) is present in all the major inflammatory cells in asthma including eosinophils, neutrophils, T-lymphocytes, macrophages and endothelial cells. Its inhibition causes down regulation of cellular activation and relaxes smooth muscle cells in the trachea and bronchus. On the other hand, inhibition of PDE III, which is present in myocardium, causes an increase in both the force and rate of cardiac contractility. These are undesirable side effects for an anti-inflammatory agent. Theophylline, a non-selective PDE inhibitor, inhibits both PDE III and PDE IV, resulting in both desirable anti- asthmatic effects and undesirable cardiovascular stimula- tion. With this well-known distinction between PDE iso- zymes, the opportunity for concomitant anti-inflammation and bronchodilation without many of the side effects asso¬ ciated with theophylline therapy is apparent. The increased incidence of morbidity and mortality due to asthma in many Western countries over the last decade has focused the clinical emphasis on the inflammatory nature of this disease and the benefit of inhaled steroids. Development of an agent that possesses both bronchodilatory and anti- inflammatory properties would be most advantageous. It ap¬ pears that selective PDE IV inhibitors should be more effective with fewer side effects than theophylline. Clin¬ ical support has been shown for this hypothesis. Attempts have therefore been made to find new compounds having more selective and improved PDE IV inhibition. Surprisingly, the present inventors have found that the analogous transformation of 3 and 3,8-disubstituted thiohypoxanthines , which themselves usually exhibit little if any activity, to the corresponding purine derivatives gives compounds having activity comparable to or in some cases greater than 6-thioxanthine derivatives of EP-A- 0256692. The preparation of 3-methyl-6-dimethylamino-3H-purine, 3-benzyl-6-methylamino-3H-purine and 3-benzyl-6-isopropyl- amino-3H-purine was reported in J.Org.Chem. , 55, 5761-5766 (1990) . No biological activity was disclosed for these compounds. It is accordingly a primary object of the present invention to provide new compounds which are effective PDE IV inhibitors. It is another object of the present invention to pro¬ vide new compounds which act as effective PDE IV inhibitors with lower PDE III inhibition. It is another object of the present invention to pro¬ vide a method of synthesizing the new compounds of this invention. It is another object of the present invention to provide a method of treating a patient requiring PDE IV inhibition. It is another object of the present invention to provide a method for treating a mammal suffering from a disease state selected from the group consisting of asthma, allergies, inflammation, depression, dementia and disease states associated with abnormally high physiological levels of cytokine(s) such as tumor necrosis factor. With the above and other objects in view, the present invention relates in part to a novel group of 3-substituted and 3,8-disubstituted 6-amino purine derivatives having bronchodilator and/or anti-inflammatory activity. The present invention therefore provides a compound of formula (I) wherein R3. Re. and R β are the same or different and each represent an H or C x . a alkyl which is unbranched or branched and unsubstituted or substituted with OH, alkoxy, C0 2 H, =N0H, =N0C0NH 2 , or =0; C 3 . 8 cycloalkyl which is unsubstituted or substituted with OH, alkoxy, halogen, haloalkyl, C0 2 H, =N0H, =N0C0NH 2 , or =0; C,_ β cycloalkylalkyl wherein the cycloalkyl portion is unsubstituted or substituted with one or more OH, alkoxy, C0 2 H, =N0H, =N0C0NH 2 , or =0; aryl which is unsubstituted or substituted with one or more Cl, NH 2 , alkylamino, dialkylamino, amido, C-.-C 8 alkylamido; and C-_-C 3 dialkyla ido OH, alkoxy, C=N0H, C=NOCONH 2/ C-.-C-. alkyl, phenyl or benzyl; aralkyl (C.- , heterocyclyl; hetero- cyclylalkyl (Ci-C ; and heteroaryl; R 6b represents a H or R 6a , or together R 6b , N, and R 6a make a C 3 -C 8 ring containing from one to three nitrogen atoms, from zero to two oxygen atoms, from zero to two sulfur atoms, optionally substituted with alkoxy, C0 2 H, C0NH 2 , =N0H, =N0C0NH 2 , =0; and where aryl is phenyl or naphthylthe heterocyclyl is a 5, 6 or 7 membered ring including from one to three nitrogen atoms, one or two oxygen atoms, zero to two sulfur atoms, and can be substituted as in aryl on the carbons or nitrogens of that ring; or a pharmaceutically acceptable salt thereof provided that when R 3 is a benzyl group, R 6a is a methyl or isopropyl group and R 6b is a hydrogen atom or R 3 , R 6a and R 6b are methyl groups, R 8 is other than a hydrogen atom. In certain preferred embodiments, R 3 represents a C ; ,_ 8 alkyl, C 3 _ 7 cycloalkyl, C,_ 8 cycloalkylalkyl, aryl or ar C*^ A )alkyl group; R 6a represents a C X . B alkyl, C 3 _ 7 cycloalkyl, C__ 8 cyclo¬ alkylalkyl, aryl ar(C-.-,)alkyl group, or heterocyclyl (C-* . .*) alkyl group; R 6b represents a hydrogen atom or a C . a alkyl, C 3 - 7 cycloalkyl, C__ s cycloalkylalkyl, aryl or ar(C 1 _ alkyl group; or -NR 6a R 6b together forms a 5-membered or 6-membered ring, which ring optionally contains one or more additional heteroatoms; and R 8 represents a hydrogen atom or a C x _ 8 alkyl, C 3 . 7 cycloalkyl, C,_ 8 cycloalkylalkyl, aryl, ar(Ci_ 4 )alkyl, pyridyl or pyridyl (Cj,_ 4 )alkyl group; For purposes of the present invention, as used herein, a Ci-g alkyl group or the C,.., alkyl moiety of an ar(C 1 _ alkyl, or alkyl group may be straight or branched chain and may be substituted or unsubstituted. A C x . β alkyl group is preferably a C- , ., alkyl group and for example methyl, ethyl, n-propyl, iso-propyl, n-butyl or isobutyl. Suitable substituents include hydroxy, alkoxy (for example methoxy or ethoxy) , halogen (for example fluorine, chlorine or bromine) and haloalkyl (for example trifluoromethyl) . A C 3 _ 7 cycloalkyl group or the cycloalkyl moiety of a C,-β cycloalkylalkyl group may preferably be a cyclobutyl, cyclohexyl or cyclopentyl group but is preferably cyclo- propyl or cyclopentyl. A C__ 8 cycloalkylalkyl group may be cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl but is preferably cyclopropyl ethyl or cyclopentylmethyl. The cycloalkyl or cycloalkylalkyl group may be substituted or unsubstituted. Suitable substituents include hydroxy, alkoxy (for example methoxy or ethoxy) , halogen (for example fluorine, chlorine or bromine) and haloalkyl (for example trifluoromethyl) . An aryl group or the aryl moiety or an ar C-..,)alkyl group is preferably phenyl. The aryl moiety may be unsub- stituted or substituted for example by a C.__ 4 alkyl group (such as methyl) or an electron-withdrawing substituent such as halogen atom (for example fluorine or chlorine) , nitro or trifluoromethyl an electron-donacting group such as alkoxy or cycloalkoxy. An ar(C 1 _ 4 ) alkyl group is preferably benzyl or substituted benzyl. The heterocyclic moiety of a heterocyclo(C 1 __)alkyl group may suitably contain one or more heteroatoms, such as oxygen or nitrogen, and conveniently is a morpholinyl group. Where -NR 6a R 6b together form a 5-membered or 6-membered ring containing an additional heteroatom, the heteroato is preferably nitrogen or oxygen. The ring formed by -NR 6a R 6b may be unsubstituted or substituted for example by a C x _ 4 alkyl group (such as methyl or ethyl) or a halogen atom (such as fluorine or chlorine) and may contain one or more units of unsaturation. Conveniently -NR 6a R 6b may be a sub¬ stituted or unsubstituted morpholine or piperazine ring. In one preferred class of compounds of formula (I) , R 3 represents a C.__ 8 (preferably C-^) alkyl group, in particular propyl, an ar(C-__ 4 ) alkyl group such as substituted or unsubstituted benzyl or a C 3 _ 7 cycloalkyl group, in particular cyclopropylmethyl. In another preferred class of compounds of formula (I) , R 6a represents a C- ^ g alkyl group such as methyl or ethyl. R 6b conveniently represents a hydrogen atom. In another preferred class of compounds of formula (I), R 6a represents a heteroaryl(C-.-C alkyl group such as 4- pyridyl ethyl group. In another preferred class of compounds of formula (I) , R 8 represents a hydrogen atom, a C 3 _ 7 cycloalkyl group, in particular cyclopropyl, or a C X . B alkyl group, in particular iso-propyl. The term "lower alkyl" is defined for purposes of the present invention as straight or branched chain radicals having from 1 to 5 carbon atoms. Likewise, the term "alkoxy" is defined for purposes of the present invention as RO where R is a straight or branched or cyclic chain radical having from 1 to 6 carbon atoms. Preferred adenine compounds according to the invention include: 3-Benzyl-6-ethylamino-3H-purine; 6-ethylamino-3- hexyl-3H-purine;8-cyclopropyl-3-cyclopropylmethyl-6-ethyl- amino-3H-purine; 6-cyclopentyl-8-cyclopropyl-3-propyl-3H- purine; 3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino- 8-isopropyl-3H-purine;8-cyclopropyl-3-propyl-6-(4-pyridyl- methylamino)-3H-purine; 6-cyclopentylamino-3-(3-cylcopen- tyloxy-4-methoxybenzyl)-8-isopropyl-3H-purine;3-(4-chloro- benzyl)-6-ethylamino-8-isoprσpyl-3H-purine;3-(4-chloroben- zyl)-6-cyclopentylamino-8-cyclopropyl-3H-purine; 3-(3- cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-3H-purine; 3- benzyl-6-ethylamino-8-(l-methylethyl)-3H-purine;3-ethyl-6- cyclopentylamino-8-cyclopropyl-3H-purine; 8-cyclopropyl-6- ethylamino-3-(3-methylbutyl)-3H-purine;3-cyclohexylmethyl- 8-cyclopropyl-6-ethylamino-3H-purine; 8-cyclopropyl-3- cyclopropylmethyl-6-ethylamino-3H-purine; 3-ethyl-6-ethyl- 5 amino-8-( (3-cyclopentyloxy-4-methoxy)benzyl)-3H-purine; 3- butyl-8-cyclopropyl-6-ethylamino-3H-purine; 8-cyclopropyl- 6-ethylamino-3-propyl-3H-purine; 3-ethyl-6-cyclopentyl- amino-8-isopropyl-3H-purine; 6-amino-8-cyclopropyl-3- propyl-3H-purine; 8-cyclopropyl-6-cyclopropylamino-3- ,10 propyl-3H-purine; 6-cyclopentylamino-8-isopropyl-3-propyl- 3H-purine; 6-(3-cyclopentyloxy-4-methoxybenzylamino)-8- cyclopropyl-3-propyl-3H-purine; 3-benzyl-6-methylamino-3H- purine; 6-butylamino-8-cyclopropyl-3-propyl-3H-purine; 3- cyclopropylmethyl-8-isopropyl-6-ethylamino-3H-purine; 8- 15 cyclopropyl-3-ethyl-6-propylamino-3H-purine; 6-cyclohexyl- amino-8-isopropyl-3-propyl-3H-purine;3 ,8-diethyl-6-morpho- lino-3H-purine; and pharmaceutically acceptable salts thereof. In certain preferred embodiments, the adenine compound 20 is selected from 3-(3-cyclopentyloxy-4-methoxybenzyl)-6- ethylamino-3H-purine (PDE IV I 50 = 2.15 μM) ; 3-(4-chloro- benzyl)-6-ethylamino-8-isopropyl-3H-purine (PDE IV I 50 = 1.13 μM) ; 3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethyl- amino-8-isopropyl-3H-purine (PDE IV I 50 = 0.32 μM) ; and 25 (particularly preferred) 6-cyclopentyl-8-cyclopropyl-3- propyl-3H-purine (PDE IV I 50 = 0.03 μM) ; and their pharma¬ ceutically acceptable salts. The present invention is also related to isoguanine compounds which are precursors of the adenine compounds 30 described above. In addition to their role as precursor compounds, it has been surprisingly discovered that these compounds also have significant PDE IV inhibitory activity. The present invention therefore is directed in part to a compound of the formula (II) wherein R 2 is O or S; and R 3 , R 6a/ R 6b and R 8 are the same or different and are represent the same groups as those set forth with respect to compound (I) above. Preferred isoguanine compounds according to the present invention include 6-cyclopentyamino-8-cyclopropyl- 3,7-dihydro-3-propyl-2-thio-2H-purin-2-one (PDE IV I 50 = 7.41μM) ; 8-cyclopropyl-3,7-dihydro-6-(2-hydroxythylamino)- 2-thio-2H-purin-2-one (PDE IV I 50 = 4.48 μM) ; (particularly preferred) 8-cyclopropyl-3,7-dihydro-6-(4-pyridylmethyl- amino)-2-thio-2H-purin-2-one (PDE IV I 50 = 0.41 μM) ; and their pharmaceutically acceptable salts. The present ' invention is also related to 2,6-dithio- xanthine compounds which are precursors of the adenine compounds described above. In addition to their role as precursor compounds, it has been surprisingly discovered that these compounds also have significant PDE IV inhibitory activity. The present invention therefore is directed in part to a compound of the formula (III) (III) wherein R 3 and R 8 are the same or different and are represent the same groups as those set forth with respect to compound (I) above. Preferred dithioxanthine compounds according to the present invention include 3-benzyl-3,7-dihydro-8-(l- methylethyl)-2,6-dithio-lH-purin-2,6-dione (PDE IV I 50 = 3.40μM) ; 3-cyclohexylmethyl-8-cyclopropyl-3,7-dihydro-2,6- dithio-lH-purin-2,6-dione (PDE IV I 50 = 3.03 μM) ; 3-(4- chlorobenzyl)-8-isopropyl-3,7-dihydro-2,6-dithio-3,7-purin- 2,6-dione (PDE IV I 50 = 2.40 μM) ; 8-cyclopropyl-3-cyclo- propylmethyl-3,7-dihydro-2,6-dithio-lH-purin-2,6-dione(PDE IV I 50 = 2.27 μM) ; 3-(3-cyclopentyloxy-4-methoxybenzyl)-3,7- dihydro-8-isopropyl-2,6-dithio-lH-purin-2,6-dione (PDE IV l 50 = 0.80 μM) ; (particularly preferred) 8-cyclopropyl-3,7- dihydro-l,3-diethyl-2,6-dithio-lH-purin-2,6-dione (PDE IV I 50 = 0.42 μM) ; and their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts are those conventionally known in the art and include, for example, acid addition salts formed with inorganic acids, such as hydrochlorides, phosphates and sulphates and with organic acids such as tartrates, maleates, fumarates and succin- ates. The adenine compounds of the present invention, as well as their isoguanine and 2,6-dithioxanthine precursors have now been shown to have PDE IV inhibitory activity using standard laboratory tests such as enzyme analysis, the guinea pig tracheal smooth muscle assay and PAF skin oedema and arachidonic acid mouse ear oedema tests and lymphocyte proliferation. These compounds may also find use in the treatment of other disease states in humans and other mammals, such as in the treatment of disease states associated with a physiologically detrimental excess of tumor necrosis factor (TNF) . TNF activates monocytes, macrophages and T-lymphocytes. This activation has been implicated in the progression of Human Immunodeficiency Virus (HIV) infection and other disease states related to the production of TNF and other cytokines modulated by TNF. Accordingly, the invention is also directed to provid- ing a compound of the invention or a pharmaceutically acceptable salt thereof for use in medicine, in particular for the treatment of conditions where a PDE IV inhibitory effect is indicated (for example chronic obstructive airway disease) . The invention further provides the manufacture of compounds of the invention or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of conditions whether a PDE IV inhibitory effect is indicated. In a further aspect, the invention provides a method of treatment of conditions where a bronchodilator or anti- inflammatory agent is indicated comprising administration of a pharmaceutically effective amount of one or more of the compounds of the invention or pharmaceutically accept- able salts thereof. The active ingredient is preferably presented as a pharmaceutical formulation, conveniently in unit dose form. According to a further aspect the invention provides a pharmaceutical composition comprising at least one com- pound of formula (I) or a pharmaceutically acceptable salt thereof formulated for administration by any convenient route. The pharmaceutical compositions of the invention can conveniently be formulated in conventional manner together with one or more pharmaceutically acceptable carriers or excipients. Compounds according to the invention may conveniently be formulated in dosage forms for oral and parenteral administration, or for administration by inhalation. For oral administration suitable dosage forms include solid dosage forms such as tablets and capsules which may be prepared by conventional pharmaceutical means with phar¬ maceutically acceptable excipients such as binders (for example starch or hydroxypropyl methyl cellulose) , lubri¬ cating agents (such as magnesium stearate or talc) , sweet- ening agents or lubricating agents. Liquid dosage forms which may be used include solutions, syrups or suspensions which may be prepared by conventional means with pharmaceu¬ tically acceptable adjuvants such as wetting agents, sus¬ pending agents, emulsifying agents and flavoring or perfum- ing agents. For parenteral administration the compounds of the invention may conveniently take the form of sterile aqueous or non-aqueous solutions, suspensions or emulsions which may contain stabilizing, suspending or dispersing agents. Compositions may also be in the form of solid compositions such as powders which may be reconstituted with a suitable vehicle such as sterile water or other sterile injectable medium before use. For administration by inhalation, the active ingred- ient may be delivered via an aerosol or nebulizer. The active ingredient may be present as a solid, a suspension or a solution. In addition, when the compounds of the present inven¬ tion are incorporated into oral dosage forms, it is contem- plated that such dosage forms may provide an immediate release of the compound in the gastrointestinal tract, or alternatively may provide a controlled and/or sustained release through the gastrointestinal tract. A wide variety of controlled and/or sustained release formulations are well known to those skilled in the art, and are contem¬ plated for use in connection with the formulations of the present invention. The controlled and/or sustained release may be provided by, e.g., a coating on the oral dosage form or by incorporating the compound(s) of the invention into a controlled and/or sustained release matrix. Specific examples of pharmaceutically acceptable car¬ riers and excipients that may be used for formulate oral dosage forms, are described in the Handbook of Pharmaceu¬ tical Excipients. American Pharmaceutical Association (1986) , incorporated by reference herein. Techniques and compositions for making solid oral dosage forms are de¬ scribed in Pharmaceutical Dosage Forms; Tablets (Lieberman, Lachman and Schwartz, editors) 2nd edition, published by Marcel Dekker, Inc. , incorporated by reference herein. Techniques and compositions for making tablets (compressed and molded) , capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences (Arthur Oxol, editor), 1553-1593 (1980), incorporated here¬ in by reference. Techniques and composition for making liquid oral dosage forms are described in Pharmaceutical Dosage Forms: Disperse Systems. (Lieberman, Rieger and Banker, editors) published by Marcel Dekker, Inc., incorp¬ orated herein by reference. The dose of the compounds of the present invention is dependent upon the affliction to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the presence of any deleterious side-effects, and the particular compound utilized, among other things. The dose of the active ingredient administered will depend on the particular compound used, the condition of the patient, the frequency and route of administration and the condition to be treated. The compounds of the inven¬ tion may conveniently be administered one or more times, for example 1 to 4 times per day. A proposed dose of the compounds of the invention is 1 to 10 mg/kg body weight, preferably 100 mg to 1000 mg per day. According to another aspect of the invention compounds of formula (I) and their pharmaceutically acceptable salts may be prepared by the following methods in which R 3 , R 6a , R 6b and R 8 are as defined for formula (I) unless otherwise indicated. According to one general process (A) compounds of formula (I) may be prepared by reacting a compound of formula (IV) with a compound of formula (V) : R 6a R 6b NH (V) The reaction of compound (IV) with (V) may convenient- ly be effected in the presence or absence of a suitable reaction medium and at a temperature of from 0 to 100°C, preferably at ambient temperature. Suitable solvents in¬ clude water, alcohol (for example ethanol) , hydrocarbons (for example benzene) and halogenated hydrocarbons (such as dichloromethane) . Compounds of formula (IV) may themselves be prepared by thionation of the corresponding 6-oxo compounds, for example, by treatment with phosphorus pentasulphide in pyridine. The thionation is suitably carried out by treat- ing a suspension of the 6-oxo compound in pyridine with a molar excess of phosphorus pentasulphide. The corresponding 6-oxo compounds may in turn be prepared from the corresponding 2-thioxanthine derivatives according to methods known in the art (see, for example, Arch Pharm, 144., 11-20 (1906), J. Org. Chem, 25, 148-149 (1960) and J. Org. Chem., 27, 2478-2491 (1962)). According to another general process (B) , compounds of formula (I) may be prepared from compounds of formula (II) : by reduction using a suitable reducing agent. The reduc¬ tion may conveniently be effected catalytically, for ex- • ample, using hydrogen in the presence of a metal catalyst such as Raney nickel. The reduction may conveniently be carried out in a suitable solvent such as an alcohol (for example ethanol) , a hydrocarbon (for example ,benzene) or water and at a suitable temperature, conveniently ambient temperature. In a particular embodiment, the Raney nickel may be prepared in situ from a nickel/aluminum alloy and a strong base such as sodium hydroxide. Alternatively', the reduction may be effected using an alkali metal, such as sodium, in liquid ammonia or hydra- zine in the presence of a base. Compounds of formula (II) may themselves be prepared from the corresponding 2,6-dithioxanthine derivatives of formula (III) : by reaction with an amine R 6a R 6b NH according to the method of process (A) above. Compounds of formula (III) in turn may be prepared from the corresponding 2-thioxanthine deriva¬ tive by thionation, for example, by treatment with phos¬ phorus pentasulphide in pyridine. The 2-thioxanthine com¬ pounds are known compounds or may be prepared from readily obtained starting materials by conventional methods. The following examples illustrate various aspects of the present invention, and are not to be construed to limit the claims in any manner whatsoever. EXAMPLE 1 3.8-Diethyl-6-morpholino-3H-purine (i) 3.8-Diethyl-hvpoxanthine 3,8-diethyl-2-thioxanthine (18.9 g) was dissolved in 370 ml of 2N NaOH Nickel aluminum alloy (75.6 g) (1.4M of Al and 0.6M of Ni) was added in portions over 1.5 hrs at 65"C. After a further 0.5 hr at 65-70'C the reaction pro¬ duct was filtered, washed with 200 ml of IN NaOH and the filtrate neutralized with 183 ml of 5N HCl to pH 7. The formed aluminum hydroxide was filtered off, the filtrate concentrated to dryness, the residue suspended in 500 ml of absolute ethanol at 90"C, and the insoluble NaCl filtered off and washed. The filtrate was concentrated to dryness, dissolved in 200 ml of chloroform, filtered and concen¬ trated to dryness again. The residue was crystallized from 150 ml of ethanol to give 3,8-di-ethyl-hypoxanthine (12.68 g) with mp (sublimation at 220°C) 305-307°C under decomposition. ( i) 3 , 8-Diethyl-6-thiohypoxanthine 5 The product of stage (i) (8.65 g) and phosphorus pentasulfide (12.0 g) was refluxed in 150 ml of pyridine for 1 hr. Under cooling 59.4 ml of 2N NaOH was added drop- wise, the solid filtered off and washed with water. The filtrate was concentrated in vacuo to dryness and the •10 residue suspended in 200 ml of water and collected. The filtrate was extracted three times with 600 ml of chloro¬ form. The residue of the organic phase was combined with the solid collected (total 6.08 g) , dissolved in 500 ml of chloroform and filtered through 24 g of silicagel. Frac- 15 tions 2 and 3 eluted 4.63 g of crude product which was crystallized from 120 ml of methanol to give 3,8-diethyl-6- thiohypoxanthine (3.58 g) with mp (sublimation at 210°C) 250-270°C under decomposition. A second crop gave 0.58 g. Elemental analysis: 20 % calc C 51.90 H 5.81 N 26.90 S 15.40 % found C 51.76 H 6.01 N 26.82 S 15.64 (iii) 3.8-Diethyl-6-morpholino-3H-purine The product of stage (ii) (52 mg) in 5 ml of morpho- 25 line was refluxed for 21 hrs. Evaporation in vacuo gave 65 mg of crude 3,8-diethyl-6-morpholino-3H-purine. EXAMPLE 2 3.8-Diethyl-6-morpholin-3H-purine 0 ( ) 3 , 8-Diethyl-2 , 6-dithioxanthine 19.14 g of 3,8-diethyl-2-thioxanthine and 22.75 g of phosphorus pentasulfide were refluxed in 280 ml of pyridine for 4.5 hrs. After cooling to room temperature 113 ml of 2N 5 NaOH were added during 15 minutes under vigorous stirring and cooling. The suspension was filtered, washed with py¬ ridine and concentrated in vacuo. The residue was suspend¬ ed in 150 ml of water and concentrated to remove the pyri¬ dine. Suspension in water and collection of the solid gave 5 the crude product, which is dissolved in 150 ml of IN NaOH, treated with two portions of 0.5 g of charcoal, and filter¬ ed. The filtrate was slowly acidified with 38 ml of 5N HC1 to pH 3 and a solid collected. The dried crude product (19.85 g) was suspended in 400 ml of 2-propanol at 95 β C. • 10 After cooling to room temperature the solid (17.62 g) is collected and washed. (ii) 3,8-Diethyl-3,7-dihydro-6- morpholino-2-thio-2H-purin-2-one 15 The product of stage (i) (14.42 g) was refluxed in 78.4 ml (900 mmoles) of morpholine for 30 hours. After cooling to room temperature the reaction product was sus¬ pended in 100 ml of acetone and the title product (16.49 g) collected and washed. 20 (iii) 3.8-Diethyl-6-morpholino-3H-purine The product of stage (ii) (7.34 g) was dissolved in 150 ml of 2N NaOH. Ni-Al alloy 50% (22.95 g) (425 mmoles of Al and 196 mmoles of Ni) was added over 1.25 hours at 65°C 25 added. After another 1.5 hours at 65-70°C additional 15 ml of ION NaOH and in portions 11.48 of Ni-Al alloy 50% was added. After another 0.5 hour at 65-70°C the reaction pro¬ duct was left over night. Dichloromethane (100 ml) was added, the suspension was filtered and the nickel washed 30 with dichloromethane (200 ml) and water (100 ml). The organic phase was separated, washed twice with water and concentrated. The residue was triturated in 50 ml of pet¬ roleum-ether to give the title product as a solid (5.40 g) mp 103-107°C. Elemental analysis: % calc C 59.75 H 7.33 N 26.80 % found C 59.64 H 7.55 N 26.35 HC1 salt crystallized from acetone has mp , (sublimation 145°C) 220-222°C. EXAMPLE 3 8-Cyclopropyl-3-ethyl-6-ethylamino-3H-purine (i) 8-Cyclopropyl-3-ethyl-6-ethylamino- 3.7-dihydro-2-thio-2H-purin-2-one 8-cyclopropyl-3-ethyl-2,6-dithioxanthine (20.19 g) prepared according to the method of example 2(i), and 70% ethylamine in water (320 ml 4.0M) were placed in a 450 ml pressure reactor and heated to 150°C for 6 hours. The reaction solution was cooled to room temperature, treated with 2 portions of charcoal (0.2 g) filtered, and evapor¬ ated to dryness. The residue was triturated in methanol (300 ml) , concentrated to about 200 ml, and the solid collected (16.48 g) , mp 265° with decomposition. (ii) 8-Cyclopropyl-3-ethyl-6-ethylamino-3H-purine The product of step (i) (11.85 g) was dissolved in 2N NaOH (270 ml) and ION NaOH (27 ml) and heated to 65°C. Within 1.25 hours 50% Ni-Al alloy (518mmoles of Ni and 1125mmoles of Al) (60.8 g) was added under vigorous stir¬ ring at 65-70°C. After a further 0-.75 hr at the same temp¬ erature the reaction mixture was cooled to room temperature and treated with chloroform (400 ml) . The nickel was fil- tered off and washed with 350 ml of chloroform and 150 ml of water. The filtrate was separated and the chloroform layer evaporated to dryness. The residue (19.64 g) was dissolved in acetone (100 ml) , treated with 2 portions of charcoal (0.15 g) filtered, and evaporated. The residue was treated with diethylether (100 ml) and crystals col¬ lected (6.10 g) , mp 80-96°C. A second crop gave 1.25 g. A recrystallized sample from diisopropylether had mp 103- 105 o C., Elemental analysis with 3.3% of water: % calc C 60.25 H 7.54 N 29.28 0 2.93 % found C 60.52 H 7.46 N 29.10 0 2.92* *(by difference) HC1 salt crystallized from methanol-acetone with mp 183- 191°C. EXAMPLE 4 A. 8-(3-cyclopentyloxy-4-methoxybenzyl. -3-ethyl-6- ethylamino-3H-purine hvdrochloride B. 8-(3-cyclopentyloxy-4-hydroxybenzyl, -3-ethyl-6- ethylamino-3H-purine (i) 3-Cyclopentyloxy-4-methoxy-benzyl alcohol To a solution of 48.70 g (220 mmoles) of 3-cyclopen- tyloxy-4-methoxybenzaldehyde in 250 ml of methanol was added portionwise 8.57 g (220 mmoles) of 97% sodium boro- hydride within 10 min at 15-22°C under cooling. After a further 20 min the methanol was removed in vacuo and the residue taken up in 10 ml of water and 300 ml of ether. The ether phase was evaporated to dryness: 48.5 g (99.2%) of liquid benzyl alcohol. (ϋ) 3-Cyclopentyloxy-4-methoxy-benzyl cyanide To a solution of 40.00 g (180 mmoles) of benzyl alco¬ hol in 530 ml of dichloromethane was added within 5 min 32.7 ml (450 mmoles) of thionyl chloride. The solution was evaporated in vacuo to dryness, which was repeated after toluene addition: 46.30 g (106.9%) of crude benzyl chlor¬ ide, which was dissolved in 230 ml of dimethylformamide and treated with 23.50 g (360 mmoles) of potassium cyanide. The mixture was heated for 4 hours to 50-55"C. The salt was filtered off and the filtrate evaporated in vacuo to dryness, which was repeated after the addition of water, the residue was taken up in ether and extracted with IN NaOH. The ether phase is evaporated to dryness to yield 41.20 g (99.0%) of crude benzyl cyanide. (iii) (3-Cyclopentyloxy-4-methoxy- phenyl.acetyl chloride 42.02 g (180 mmoles) of benzyl cyanide were refluxed in 410 ml of 94% ethanol, 106 ml of water, and 180 ml of ION NaOH for 20 hours. The ethanol was removed in vacuo, the solution diluted to 800 ml with water, repeated twice with 2 g of charcoal, filtered, and acidified with 185 ml of ION HC1. The acid crystallized slowly, was collected and dried at 30°C: 42.2 g (92.9%) of acid. 1.51 g (2.3%) could be extracted by ether from the filtrate. Both parts (173 mmoles) are combined and refluxed in 500 ml of di¬ chloromethane and 31.4 ml (433 mmoles) of thionyl chloride for 1.5 hours. The solution was treated twice with 2 g of charcoal, filtered and evaporated to dryness. This was repeated twice with little toluene: 48.70 g (>100%) of crude acetyl chloride as a reddish liquid. (iv) 8-(3-Cyclopentyloxy-4-methoxy- benzyl. -3-ethyl-2-thioxanthine 10.02 g (45 mmoles) of 5,6-diamino-l-ethyl-2-thio- uracil hydrochloride was dissolved in 200 ml of pyridine, treated with 6.05 g (57 mmoles) of sodium carbonate and 15.5 -g (56 mmoles) of Example 4 (iii) dissolved in 25 ml of ether added within 10 minutes at 5-10°C. After 1.5 hours at room temperature the solid was filtered off and the filtrate evaporated in vacuo to dryness. The residue was dissolved in 100 ml of 2N NaOH and 200 ml of water and brought to reflux, within 1 hour 70 ml are distilled off. The solution was filtered and neutralized to pH 7.5 with 52 ml of 5N HC1. The solid was collected and dried: 14.37 g (79.7%) of crude 2-thioxanthine (from the water 4.2 g of the phenyl acetic acid was recovered) , which was suspended in 250 ml of hot methanol and collected again: 10.68 g (59.3%) of purified 2-thioxanthine, which was dissolved is 100 ml of IN NaOH and filtered. The filtrate was acidified to pH 6 and the solid collected: 8.82 g (48.9%) of 2-thio- xanthine with mp (260°C) 280-310°C under decomposition. (v) 8-(3-Cyclopentyloxy-4-methoxy- benzyl. -3-ethyl-2,6-dithioxanthine 8.41 g (21 mmoles) of 2-thioxanthine are refluxed with 5.60 g (25.2 mmoles) of phosphorus pentasulfide in 80 ml of pyridine. After 5.5 hours 27.7 ml (55.4 mmoles) of 2N NaOH were added at 5-10°C. The solid was filtered off and wash¬ ed with pyridine. The filtrate was evaporated in vacuo to dryness, the residue is suspended in 200 ml of water with little tetrahydrofuran (THF) for crystallization, the sus¬ pension is concentrated and the solid at pH 8 collected and washed. Redissolution in 100 ml of 0.5 N NaOH, treatment with charcoal (20%) , filtration and acidification to pH 6 yielded the solid crude dithixanthine 7.84 g (89.6%). Crystallization from chloroform and suspension in hot meth¬ anol gave 5.31 g (60.7%) of dithioxanthine with mp 241-3°C. The mother liquors were combined (2.36 g) and filtered with chloroform through 60 g of silicagel in a column: 1.73 g (19.8%) were isolated as a second crop. (vi) 8-(3-Cyclopentyloxy-4-methoxy-benzyl)-3-ethyl -6-ethylamino-3.7-dihvdro-2-thio-2H-purine-2-one 6.67 g (16 mmoles) of dithioxanthine and 52 ml of 70% ethylamine in water were heated to 150°C in a pressure re- actor (250 psi) for 12 hours under nitrogen. The solution was treated with charcoal (5%) , filtered, and evaporated in vacuo to dryness. The residue was suspended in water, acidified with IN HC1 to pH 4 and neutralized to pH 8 with sodium bicarbonate. The solid was collected, washed and dried to give 6.66 g (97.4%) of crude thioisoguanine. (vii) 8-(3-Cyclopentyloxy-4-methoxy-benzyl)-3- ethyl-6-ethylamino-3H-purine hvdrochloride 6.41 g (15 mmoles) of crude thioisoguanine and 9.70 g (165 mmoles) of neutral Raney-nickel were refluxed in 70 ml of 1-propanol for 3 hours. The nickel was filtered off and the filtrate evaporated in vacuo to dryness. The residue (5.86 g/98.8%) was dissolved in chloroform and extracted extensively with IN NaOH. The NaOH solution was acidified with 5N HCl to pH 4 and neutralized with sodium bicarbonate to pH 7.5. An oil precipitated, which crystallized slowly and the solid collected: 0.49 g of 8-(3-cyclopentyloxy-4- hydroxylbenzyl)-3-ethyl-6-ethylamino-3H-purine with mp 172- 4°C. The chloroform solution was evaporated to dryness: 3.76 g (63.4%) of crude 3H-purine, which was dissolved in 30 ml of methanol and treated with 10 ml of IN methanolic HCl. The solution was evaporated in vacuo to dryness and the residue crystallized from acetone-ethyl acetate: 3.66 g (56.5%) of 8-(cyclopentyloxy-4-methoxybenzyl)-3-ethyl-6- ethylamino-3H-purine hydrochloride with mp 169-71°C. Elemental analysis for C, ? H..,C1N.*0. Calc. C 61.17 H 7.00 N 16.21 Found C 61.09 H 6.77 N 16.18 EXAMPLE 5 3-(3-cyclopentyloxy-4-methoxybenzyl)-6- ethylamino-8-isopropyl-3H-purine hvdrochloride (i) 3-Cyclopentyloxy-4-methoxy-benzaldehvde 77.70 g (500 mmoles) of isovanillin and 69.40 g (600 mmoles) of 97% potassium t-butoxide (t-BuOK) dissolved in 800 ml of 1-propanol, 69.0 ml 630 mmoles), and the solution refluxed. After 3 hours another 9.25 g (80 mmoles) of t- BuOK were added at 80°C and the suspension refluxed for another 3 hours. The solid was filtered off and the fil¬ trate evaporated in vacuo to dryness. The residue was dis- solved in ether and extracted with IN NaOH. The ether phase was evaporated to dryness: 85.40 g (77.5%) of cyclopentyl- oxybenzaldehyde was isolated. (ii) 3-Cyclopentyloχy-4-methoxy-benzaldehyde-oxime 85.4 g (388 mmoles) of 3-cyclopentyloxy-4-methoxy- benzaldehyde were dissolved in 350 ml of 94% ethanol and added within 10 minutes at 15-20°C to a solution of 29.7 g (427 mmoles) of hydroxylammonium chloride and 52.8 g (388 mmoles) of sodium acetate trihydrate (3 H 2 0) in 230 ml of water. After 2 hours the ethanol was removed in vacuo, the residue treated with 16.3 g (194 mmoles) of sodium bicar¬ bonate until CO, formation ceased and extracted with ether. Evaporation of the ether phase gave 91.0 g (99.7%) of oxime as a mixture of the 2 isomers. (iii) 3-Cyclopentyloxy-4-methoxy-benzylamine 73.5 g (320 mmoles) of oxime, 80 ml of methanol, 55 g of liquid ammonia, and 18.5 g of neutral Raney-nickel are placed into a 450 ml pressure reactor. Hydrogen gas was added up to a pressure of 1,200 psi and the whole heated to 75-80°C, when the pressure dropped to 600 psi hydrogen gas was added again to 1,200 psi. After 4 hours the pressure reached 1080 psi and remained constant. The nickel was filtered off and washed with methanol. The filtrate is evaporated to dryness, dissolved in ether and extracted with IN NaOH. The ether phase was evaporated to dryness: 68.9 g (97.3%) of benzylamine. (iv) 3-Cyclopentyloxy-4-methoxy-benzyl-isothiocvanate 82.3 g (372 mmoles) of benzylamine were dissolved in 10 ml of toluene and added at 15-20"C (with cooling) within 20 minutes to an emulsion of 22.5 ml (372 mmoles) of carbon disulfide and 14.88 g (372) mmoles) of NaOH in 52 ml of water. The reaction mixture was heated to 75-80°C for 1 hour and cooled to 40°C. Within 15 minutes, 35.4 ml (372 mmoles) of ethyl chloroformate were added at 40-45"C. The emulsion was brought to about pH 8 with 2N NaOH and heated to 55-60°C, gas formation ceased after about 10 hours keep¬ ing the pH at 8 with 2N NaOH (total about 8 ml) . The 5 organic layer was collected and the solvent evaporated: 96.3 g (98.3%) of benzyl isothiocyanate. (v) l-(3-Cvclopentyloxy-4-methoxy-benzyl. -2-thiourea 96.3 g (366 mmoles) of benzylisothiocyanate were ■ 10 dissolved in 100 ml o THF and treated with 44.2 ml (732 mmoles) of 32% ammonia solution. After 0.5 hour at 40- 45°C, 300 ml of water were added and the THF removed in vacuo. The gummy suspension is treated with 200 ml of ether, the crystals collected and washed with water and 15 ether. Suspension in 30 ml of methylenechloride and collection gave 65.77 g (64.2%) of benzyl-2-thiourea with mp 144-5°C. (vi) 6-Amino-l-(3-cyclopentyloxy-4- 20 methoxy-benzyl-2-thiouracil 29.65 g (256 mmoles) of 97% t-BuOK were dissolved in 240 ml of 2-propanol. 65.33 g (233 mmoles) of 2-thiourea and 25.3 ml (238 mmoles) of ethyl cyanoacetate were added at 80 β C. After 30 minutes at reflux a solution was formed 25 and after 4.5 hours an additional 2.96 g (25.6 mmoles) of t-BuOK and 4.97 ml (46.6 mmoles) of ethyl cyanoacetate add¬ ed. After 22 hours of refluxing the solid was collected, combined with the residue of the filtrate, dissolved in 1 1 of water and precipitated with about 50 ml of 5N HCl (pH 30 3-4) . The solid is collected, washed, dried, recrystal- lized by suspension in 1 1 of refluxing acetone, concen¬ trated to about 300 ml and collected at 23°C: 80.65 g (85.7%) of uracil containing 1 equivalent of acetone, mp 225-7°C. (vii) 6-Amino-l-(3-cyclopentyloxy-4- methoxy-benzyl. -5-nitroso-2-thiouracil 68.9 g (170 mmoles) of uracil are dissolved in 650 ml of acetic acid, for removal of acetone 100 ml are distilled off in vacuo, and at 65-70°C 43.4 ml (174 mmoles) of 4N sodium nitrite solution were added within 10 minutes. After further 5 minutes the suspension was cooled to 30°C and diluted with 1.7 1 of water. The solid was collected, washed, and dried: 64.08 g (100%) of nitrosouracil, which was dissolved in 330 ml of IN NaOH and 300 ml of water, filtered, and acidified with 5N HCl to pH 2, to keep it in suspension 2 1 of water were added. The solid was collec¬ ted and washed, suspended in 60 ml of methanol and collec¬ ted again: 54.2 g (84.7%) of nitrosouracil. (viii) 1-(3-cyclopentyloxy-4-methoxy- benzyl. -5.6-diamino-2-thiouracil 15.06 g (40 mmoles) of nitrosouracil are suspended in 300 ml of THF and hydrogenated with hydrogen gas and 6 g of neutral Raney-nickel for 2.5 hours, when hydrogen uptake ceased. After 1 hour all was dissolved and thereafter a new precipitate formed, which is dissolved in a mixture of methylenechloride and methanol. The nickel was filtered off and the filtrate evaporated in vacuo to dryness: 13.96 g (96.3%) of crude diaminouracil. (ix) 6-Amino-l-(3-cyclopentyloxy-4-methoxy- benzyl, -5-isobutyryl-amino-2-thiouracil A two phase solution of 15.01 g (41.4 mmoles) of di- aminouracil, 180 ml of THF, 150 ml of water, 6.96 g (82.8 mmoles) of sodium bicarbonate, and 10.52 ml (62.1 mmoles) of isobutyric anhydride is heated to 55"C under nitrogen for 1 hour. The THF was evaporated in vacuo and the resi¬ due diluted with 200 ml of water (pH 8) . The solid was collected, washed, and dried: 16.25 g (90.7%) of isobu- tyrylaminouracil. (x) 3-(3-Cyclopentyloxy-4-methoxy- benzyl)-8-isopropyl-2-thioxanthine 17.81 g (41.2 mmoles) of isobutyrylaminouracil were refluxed for 0.75 hour in 120 ml of IN NaOH and 80 ml of water. The solution was treated twice with 0.5 g of char¬ coal, filtered, acidified with 5N HCl, and put to pH 7-8 with sodium bicarbonate solution. The solid was collected, washed, and dried: 15.31 g (89.6%) of 2-thioxanthine with mp 270-6°C (with decomposition). (xi) 3-(3-Cyclopentyloxy-4-methoxy- benzyl)-8-isopropyl-2.6-dithioxanthine 15.17 g (36.6 mmoles) of 2-thioxanthine and 9.76 g (43.9 mmoles) of phosphorus pentasulfide were refluxed under nitrogen in 140 ml of pyridine for 5.5 hours. At 5- 10°C 48.3 ml (96.6 mmoles) of 2N NaOH were added dropwise. The solid was filtered of and washed with pyridine. The filtrate was evaporated in vacuo to dryness and treated with 300 ml of water. The suspension was adjusted to pH 7 with sodium bicarbonate solution and the solid collected, washed, dissolved in 200 ml of 0.5N NaOH solution, treated twice with 1.6 g of charcoal, filtered, acidified with 5N HCl and neutralized with sodium bicarbonate solution to pH 7. The solid was collected, washed, and dried: 14.64 g (92.9%) of crude dithioxanthine, which was dissolved in 400 ml of methylenechloride and filtered through 60 g of sili¬ cagel in a column. The solvent was evaporated and the residue suspended in 20 ml of 100% ethanol and collected: 14.34 g (82.2%) of dithioxanthine with mp 204-6°C (contain- ing 1 mol EtOH) . (xii) 3-(3-Cyclopentyloxy-4-methoxy-benzyl)-6-ethyl- 3.7-dihvdro-8-isopropyl-2-thio-2H-purin-2-one 6.20 g (13 mmoles) of dithioxanthine and 42 ml of 70% ethylamine in water were placed into a 450 ml pressure reactor and heated to 150°C (240 psi) for 12 hours. The solution was filtered and evaporated to dryness. The resi¬ due was suspended in water, acidified with IN HCl to pH 3, and neutralized with sodium bicarbonate solution to pH 7-8. The solid was collected, washed, and dried: 5.48 g (95.5%) of thioisoguanine with mp 72-7°C. (xiii) 3-(3-Cyclopentyloxy-4-methoxybenzyl)-6- ethylamino-8-isopropyl-3H-purine hvdrochloride 5.43 g (12.3 mmoles) of thioisoguanine and 7.9 g of neural Raney-nickel were refluxed in 60 ml of 1-propanol for 4.5 hours. The nickel was filtered off and the fil¬ trate evaporated in vacuo to dryness: 4.90 g (97.2%) of crude purine, which was dissolved in 20 ml of chloroform, extracted with IN NaOH and filtered through 30 g of sili- cagel in a column. The solvent was evaporated, the residue dissolved in 25 ml of methanol, treated with 11 ml of meth¬ anolic IN HCl solution and evaporated to dryness. The res¬ idue was suspended in 80 ml of ethyl acetate and collected: 3.49 g (63.6%) of 3H-purine hydrochloride with mp 202-12°C. Elemental analysis for C..H7 ? C1N.0 ? Calc. C 61.94 H 7.23 N 15.70 0 7.17 Found C 62.17 H 7.02 N 15.66 0 7.30 EXAMPLE 6 3-(3-Cyclopentyloxy-4-methoxybenzy1)- 6-ethylamino-3H-purine hvdrochloride (i) 3-(3-Cyclopentyloxy-4-meth- oxybenzyl. -2-thioxanthine 14.62 g (40 mmoles) of l-(3-cyclopentyloxy-4-methoxy- benzyl)-5,6-diamino-2-thiouracil were dissolved in 200 ml of formic acid. The solution was concentrated in vacuo at room temperature to remove the water. 50 ml of formic acid were added and the procedure repeated. After a total of 1 hour the formic acid solution was concentrated to 30 ml at 25° and diluted with 300 ml of water. The crystals were collected, washed, and dried: 13.48 g (86.3%) of crude 5- formamide (mp 210-30°C) , which was refluxed in 86 ml of IN NaOH for 15 min. The turbid solution was treated twice with 0.6 g of charcoal, filtered, acidified with 5N HCl to pH 2, and neutralized to pH 6.5. The amorphous solid was 5 collected, washed, and dried at 60°C: 11.93 g (80.1%) of crude 2-thioxanthine, which was dissolved in 150 ml of THF, treated with charcoal (5%) , filtered, concentrated to 40 ml, and diluted with 250 ml of ethanol. After concentra¬ tion to 120 ml the formed solid is collected, washed, and •10 dried: 9.21 g (61.9%) of 2-thioxanthine with mp 254-65°C. Elemental analysis for C 1 .H..,N,.O.S Calc. C 58.05 H 5.41 N 15.04 0 12.89 Found C 58.13 H 5.41 N 14.93 0 13.11 15 (ii) 3-(3-Cyclopentyloxy-4-methoxy- benzyl. -2.6-dithioxanthine 8.94 g (24 mmoles) of 2-thioxanthine and 6.40 g (28.8 mmoles) of phosphorus pentasulfide were refluxed in 96 ml of pyridine under nitrogen for 1.5 hours. At 5-10°C 31.7 20 ml (63.4 mmoles) of 2N NaOH were added under cooling and the mixture diluted with 30 ml of pyridine. The solid was filtered off and the filtrate evaporated in vacuo to dry¬ ness. The residue was suspended in 30 ml of water and the solid collected, dissolved in 160 ml of 0.5N NaOH, filter- 25 ed, treated with charcoal (20%) , filtered again, acidified with 5N HCl to pH 5, the solid collected, washed, and dried: 9.03 g (96.9%) of crude dithioxanthine. The product was dissolved in 400 ml of chloroform and filtered through 30 g of silicagel in a column. The solvent was removed in 30 vacuo, the residue dissolved in 50 ml of THF, filtered, concentrated to 30 ml, diluted with 200 ml of ethanol, con¬ centrated again to 150 ml and the solid collected, washed, and dried: 8.65 g (92.8%) of dithioxanthine with mp 215- 8°C. Elemental analysis for C 18 H 20 N 4 O 2 S 2 with 0 . 25M of ethanol and 0. 5M of water Calc . C 54 . 32 H 5. 54 N 13 .70 0 10. 76 Found C 54 . 67 H 5. 32 N 13 . 80 0 10 . 20 (iii) 3-(3-Cyclopentyloxy-4-methoxy-benzyl)- 3,7-dihvdro-2-thio-2H-purine-2-one 4.66 g (12 mmoles) of dithioxanthine and 48.3 ml (60 mmoles) of 70% ethylamine in water were heated to 150"C in a 450 ml pressure reactor under N 2 for 12 hours (240 psi) . The solution was treated with charcoal (5%) , filtered and evaporated to dryness. The residue was taken up in 100 ml of water, acidified with IN HCl to pH 3 and neutralized with sodium bicarbonate to pH 7, and the solid collected: 4.43 g (92.5%) of crude thioisoguanine with mp 99-103°C. (iv) 3-(Cyclopentyloxy-4-methoxy-benzyl)- 6-ethylamino-3H-purine hvdrochloride 4.39 g (11 mmoles) of thioisoguanine and 7.10 g (121 mmoles) of neutral Raney-nickel are refluxed in 50 ml of 1- propanol for 4.5 hours. The nickel was filtered off and the filtrate evaporated to dryness. The residue (3.79 g/93.8%) was dissolved in 20 ml of chloroform and 0.4 ml methanol and filtered through 24 g of silicagel in a column also with 2% methanol. The combined fractions were washed with IN NaOH and the organic phase evaporated to dryness. The residue (2.69 g/66.6%) was dissolved in 30 ml of di¬ chloromethane and 0.6 ml methanol and again filtered through 30 g of silicagel. A total of 1.86 g (46.0%) of 3H-purine was isolated, which was dissolved in 20 ml of methanol, treated with 5.4 ml of IN methanolic HCl, and evaporated in vacuo to dryness. Crystallization and re- crystallization from dichloromethane and ethyl acetate gave 1.75 g (39.4%) of 3H-purine hydrochloride with mp 170-85°C. Elemental analysis for C.r.H,_.C-N-,0.- Calc. C 59.47 H 6.49 N 17.34 O 7.92 Found C 59.72 H 6.44 N 17.25 O 8.24 EXAMPLE 7 8-Cyclopropyl-6-(4-pyridylmethyl- amino. -3-propyl-3H-purine dihvdrochloride (i) 8-Cyclopropyl-3-propyl-2,6-dithioxanthine in a 5 L 3-necked flask fitted with a mechanical stirrer and a condenser with a drying tube were placed 2.2 L of pyridine and 8-cyclopropyl-3-propyl-2-thio-6-oxo- xanthine (220 g, 0.88 mol) . Phosphorus pentasulfide (236 g, 1.06 mol) was added and the mixture was heated under reflux for 5 hours and stored overnight at room temper¬ ature. The reaction mixture was cooled to 5-10° and 3 N aqueous sodium hydroxide (770 ml) was added over 1.5 hours with stirring. Stirring was continued for 30 minutes after removal of the cooling bath and the precipitated product was collected by suction filtration. The filter cake was washed successively with pyridine (300 ml) and four 300 ml portions of tetrahydrofuran. The solid material was stir¬ red with water (750 ml) , filtered and washed with water. The crude product was dissolved in 1.7 L of 1 N sodium hydroxide and stirred with 15 g of Darco G-60. The char¬ coal was filtered and the treatment was repeated with a freshi portion of charcoal. The solution was acidified to pH 1.5 with 6 N hydrochloric acid and the pale yellow precipitate was collected. The solid was dissolved again in 1.7 L of IN sodium hydroxide and treated successively with two portions of charcoal as above. The solution was acidified and the precipitate was collected and washed with water. After drying to constant weight at 54"C under vacuum, there was obtained 128 g (56%) of the title com- pound, mp over 245°C. (ii) 8-cyclopropyl-3,7-dihydro-6-(4-pyridyl- methylamino-3-propyl-2-thio-2H-purin-2-one 5.33 g (20 mmoles) of 8-cyclopropyl-3-n-propyl-2,6- dithioxanthine and 21.3 ml (200 mmoles) of 95% 4-picolyl- 5 amine were heated under argon to 150-5°C. After 14 hours the cooled solution was poured into 100 ml of water, acidified with 19 ml of ION HCl and IN HCl to pH 6, where an orange colored gum was formed. With sodium bicarbonate the mixture was neutralized to pH 7. With time the gum ,10 crystallized and the solid is collected and washed. The residue was suspended in acetone and the crystals collec¬ ted: 3.92 (57.6%) of crude product. The filtrate was evaporated to dryness, dissolved in 40 ml of 0.5N NaOH, extracted 4 times with methylenechloride, and acidified 15 again with 5N HCl to pH 6. Again the gum crystallized over 48 hours and the mixture was neutralized to pH 7 with bi¬ carbonate and the solid collected: 1.75 g (25.7%) of crude product. Both parts were dissolved in 30 ml of methylene¬ chloride and filtered through 30 g of silicagel in a 20 column. 150 mg (2.8%) of starting material was recovered first, then 5.04 g (74.0%) of product was recovered with 5% of methanol, which was dissolved in 32 ml of IN HCl, treat¬ ed with 250 mg of charcoal, filtered, and neutralized with 7.5 ml of 2N NaOH and sodium bicarbonate solution to pH 7- 25 8. The water phase was decanted from the gum and the latter washed with water and crystallized from acetone: 4.08 g (59.9%) of thioisoguanine with mp 204-210°C with decomposition. 30 (iii) 8-Cyclopropyl-6-(4-pyridylmethylamino)- 3-propyl-3H-purine dihydrochloride 3.06 g (9 mmoles) of thioisoguanine and 5.8 g of neutral Raney-nickel were refluxed under argon in 1- propanol for 4 hours. The nickel was filtered off and 35 washed with methanol. The filtrate as evaporated to dryness, the residue dissolved in 20 ml of* methylene- chloride, the solution extracted with IN NaOH, and evaporated to dryness: 2.43 g (87.4%) of crude purine, which was dissolved in 20 ml of methanol, treated with 17 ml of IN methanolic HCl and evaporated again to dryness. Crystallization from isopropanol gives 1.09 g (36.3%) of purine dihydrochloride with mp 157-65"C. EXAMPLE 8 6-Cyclopentylamino-8-cyclopropyl- 3-propyl-3H-purine hvdrochloride (i) 6-Cyclopentyl-8-cyclopropyl-3,7- dihvdro-3-propyl-2-thio-2H-purine-2-one 5.33 g (20 mmoles) of 8-cyclopropyl-3-n-propyl-2,6- dithioxantine and 42 ml of cyclopentylamine were heated in a 450 ml pressure reactor to 150°C (50 psi) with the ex¬ clusion of air. After 20 hours the solution was transfer¬ red with methanol to a round bottom flask and evaporated in vacuo to dryness. The residue was crystallized from ace¬ tone: 1.07 g (15.1) of thioisoguanine hydrochloride with mp 196-98°C. The mother liquor was dissolved in methylene¬ chloride, extracted with sodium bicarbonate solution and filtered through 45 g of silicagel on a column. The first unpolar 0.54 g were discarded and the rest gave 4.63 g (72.9%) of the crude isoguanine as a gum. (ii) 6-Cyclopentylamino-8-cyclopropyl- 3-n-propyl-3H-purine hvdrochloride 4.49 g (14.1 mmoles) of thioisoguanine and 9.2 g of neutral Raney-nickel were refluxed in 45 ml of 1-propanol for 5 hours. The nickel was filtered off and the filtrate evaporated to dryness. The residue (>100%) was dissolved in 30 ml of methanol, treated with 16.9 ml of IN methanolic HCl solution, and evaporated to dryness. The residue was dissolved in methylenechloride, treated with 0.12 g of charcoal, filtered, concentrated, diluted with acetone and the remaining methylene chloride removed by distillation. The crystals were collected: 1.04 g (22.9%) of purine hydrochloride with mp 218-221°C, a second crop gave 0.61 g (13.4%) . Elemental analysis for C- 6 H 24 C-.N 5 321.86 89% + 11% CH.C1, Calc. C 54.70 H 6.95 N 19.37 Cl 18.98 Found C 54.84 H 6.71 N 19.05 Cl 19.40 (diff) EXAMPLE 9 - ISOGUANINE DERIVATIVES Following the previously set forth methods, the fol¬ lowing isoguanine derivatives of the present invention were synthesized. The chemical name and melting point are provided in Table 1 below. TABLE 1 A. 3 , 8-diethyl-3 , 7-dihydro-6-morpholino-2-2-thio- purin-2-one melting point: 295-298'C (with decomposition). Elemental analysis: Calc. C 53.22 H 6.53 N 23.87 S 10.93 Found C 53.01 H 6.77 N 23.82 S 10.97 B. 3-(cyclopropylmethyl) -3 , 7-dihydro-8-isopropyl-6- propylamino-2-thio-2H-purin-2-one Melting point: 208-210°C Elemental analysis: Calc. C 62.26 H 8.01 N 24.20 Found C 62.34 H 8.06 N 23.89 EXAMPLE 11 - PDE IV INHIBITION BY ISOGUANINE COMPOUNDS The PDE IV inhibitory activity of certain of the fore- going isoguanine compounds was determined according to the procedures set forth below. The results are provided in Table 2. Type IV Phosphodiesterase Enzyme Isolation Protocol The Type IV PDE is isolated from bovine tracheal smooth muscle using a procedure similar to that previously described by Silver, P.J., Hamel, L.T., Perrone, M.H. Bentley, R.G. Bushover, C.R., Evans, D.B.: Eur. J. Pharmacol. 150:85,1988.(1). Briefly, smooth muscle from bovine trachea is minced and homogenized using a polytron in 10 volumes of an extraction buffer containing 10 mM Tris-acetate (pH 7.5), 2 mM magnesium chloride, l mM dithiothreitol and 2,000 units/ml of aprotinin. This and all subsequent procedures are performed at 0-4 ° C . The homogenate is sonicated and then centrifuged at 48,000 x g for 30 minutes. The resulting supernatant is applied to a DEAE Trisacryl M column previously equilibrated with sodium acetate and dithiothreitol. After applications of the sample, the column is washed with sodium acetate/dithiothreitol, after which the different forms of PDE are eluted from the column using a linear Tris-HCl/NaCl gradient. Fractions containing Type IV PDE are collected, dialyzed and concentrated to 14% of the original volume. The concentrated fractions are diluted to 50% with ethylene glycol and stored at -20 o C. Measuring Type IV PDE Activity Enzyme activity is assessed by measuring the hydroly¬ sis of [ 3 H]-cyclic AMP, as described by Thompson, W.J., Teraski, W.L. , Epstein, P.N., Strada, S.J.: Adv. Cyclic Nucleotide Res. 10:69, 1979. The cyclic AMP concentration used in this assay is 0.2 μM, which approximates the K__ value. Protein concentration is adjusted to ensure that no more than 15% of the available substrate is hydrolyzed during the incubation period. All test compounds are dissolved in dimethyl sulfoxide (final concentration of 2.5%). This concentration of di¬ methyl sulfoxide inhibits enzyme activity by approximately 10%. EXAMPLE 12 - ADENINE DERIVATIVES Following the method of the above Examples, the fol¬ lowing compounds were similarly prepared from the appro¬ priate starting materials. All temperatures are in °C unless otherwise stated. The data is provided in Table 3 below. EXAMPLE 13 ELEMENTAL ANALYSIS OF ADENINES Elemental analysis was conducted for certain of the compounds set forth in the above tables. The results are provided below. Elemental analysis for 8-cyclopropyl-3- ethyl-6-ethylamino-3H-purine hydrochloride 89% + 1% HCl + ? Calc. C 53.29 H 6.80 N 25.00 O 0.53 Found C 52.97 H 7.01 N 26.01 0 0.34 Elemental analysis for 6-ethylamino-3-hexyl-3H-purine mo 188-94" Calc. C 55.02 H 7.81 N 24.68 Cl 12.49 Found C 55.33 H 8.05 N 24.50 Cl 12.71 Elemental analysis for 3-hexyl- 6-methyl-amino-3H-purine hydrochloride mp 190-195° Calc. C 53.43 H 7.47 N 25.96 Cl 13.14 Found C 53.70 H 7.81 N 25.92 Cl 13.18 Elemental analysis for 3-benzyl- 6-methylamino-3H-purine hvdrochloride Calc. C 56.63 H 5.12 N 25.40 Cl 12.86 Found C 56.84 H 7.81 N 25.92 Cl 13.18 Elemental analysis for 8-cyclopropyl-6-ethyl- amino-3-(3-methylbutyl. -3H-purine hvdrochloride Calc. C 58.15 H 7.81 N 22.60 Cl 11.44 Found C 58.12 H 8.01 N 22.65 Cl 11.46 Elemental analysis for 8-cyclopropyl-3- ethyl-6-propylamino-3H-purine hvdrochloride Calc. C 55.41 H 7.15 N 24.85 Cl 12.58 Found C 55.74 H 7.06 N 25.08 Cl 12.71 Elemental analysis for 8-cyclo- propyl-3-ethyl-6-methylamino-3H-purine Elemental analysis for 3-butyl-6- ethylamino-3H-purine hydrochloride mp 221-227° Calc. C 51.65 H 7.09 N 27.38 Cl 13.88 Found C 51.74 H 7.06 N 27.62 Cl 13.93 Elemental analysis for 3-butyl-8-cyclo- propyl-6-ethylamino-3H-purine hvdrochloride p 194-196° Calc. C 56.83 H 7.49 N 23.67 Cl 11.98 Found C 56.91 H 6.98 N 23.97 Cl ? Elemental analysis for 6-ethylamino-3-propyl-3H-purine 98% + 2% water Calc. C 57.35 H 7.44 N 33.44 Found C 57.68 H 7.22 N 33.29 Elemental analysis for 8-cyclopropyl-6- ethylamino-3-propyl-3H-purine hydrochloride Calc. C 55.41 H 7.15 N 24.85 Cl 12.38 Found C 55.45 H 7.13 N 24.96 Cl 12.71 Elemental analysis for 8-cyclopropyl-3- cvcloproprylmethyl-6-ethylamino-3H-purine hydrochloride Calc. C 57.23 H 6.87 N 23.84 Cl 12.07 Found C 57.49 H 6.88 N 23.59 Cl 12.49 Elemental analysis for 3-benzyl-6-ethylamino-3H-purine Calc. C 66.39 H 5.97 N 27.65 Found C 66.58 H 5.63 N 27.80 Elemental analysis for 8-cyclopropyl-6- cvclopropylamino-3-propyl-3H-purine hydrochloride Calc. C 57.23 H 6.86 N 23.84 Cl 12.07 Found C 57.30 H 6.90 N 23.77 Cl 12.16 Elemental analysis for 3-cyclopropyl- 6-ethylamino-3H-purine hvdrochloride Calc. C 56.84 H 7.50 N 23.67 Cl 11.98 Found C 56.82 H 7.54 N 23.65 Cl 12.05 Elemental analysis for 3-benzyl-6- ethylamino-8-(1-methylethyl. -3H-purine hvdrochloride Calc. C 61.52 H 6.68 N 21.10 Cl 10.68 Found C 61.52 H 6.59 N 21.18 Cl 10.60 Elemental analysis for 3-cyclohexylmethyl-8- cvclopropylmethyl-6-ethylamino-3H-purine hvdrochloride Calc. C 60.79 H 7.80 N 20.85 Cl 10.56 Found C 60.55 H 7.48 N 20.85 Cl 11.34 Elemental analysis for 3-cyclopropylmethy-8- isopropyl-6-ethylamino-3H-purine hvdrochloride Elemental analysis for 3-ethyl-8- isopropyl-6-ethylamino-3H-purine hvdrochloride Elemental analysis for 3-ethyl-8- isopropyl-6-ethylamino-3H-purine hvdrochloride Elemental analysis for 3-ethyl-8- cvclopentyl-6-benzylamino-3H-purine hvdrochloride Calc. C 63.78 H 6.76 N 19.57 Found C 63.55 H 6.54 N 19.51 Elemental analysis for 3-ethyl-8- cvclopentyl-6-ethylamino-3H-purine hvdrochloride Elemental analysis for 3,8-diethy-3,7- dihvdro-6-morpholino-2-thio-2H-purin-2-one Elemental analysis for 3-(cyclopropylmethyl)-3,7- dihvdro-8-isopropyl-6-propylamino-2-thio-2H-purin-2-one Elemental analysis for 6-cyclopentylamino-8-cyclopropyl- 3.7-dihvdro-3-propyl-2-thio-2H-purin-2-one hydrochloride Elemental analysis for 6-butylamino-8-cyclo- propyl-3.7-dihydro-3-propyl-2-thio-2H-purin-2-one EXAMPLE 14 - PDE IV INHIBITION BY ADENINE COMPOUNDS The PDE IV inhibitory effect of certain of the com¬ pounds set forth above was examined according to the methods previously described. The results are provided in Table 4 below. EXAMPLE 15 Dithioxanthine derivatives of the present invention were manufactured and analyzed. The results are set forth in Table 5 below. EXAMPLE 16 - PHARMACOLOGICAL TESTS Isolated Guinea Pig Trachea The test compound was dissolved in dimethylsulfoxide. Guinea pig isolated trachealis muscle was mounted in a bath containing Krebs solution maintained at 37.5°C and bubbled with carbogen (95% 0 2 , 5% C0 2 ) . Tension changes were recorded isometrically using force displacement transducers in conjunction with potentiometric pen recorders.8 The ability of the test compounds to relax airways muscle was investigated by the construction of cumulative concentration effect cuNes. Each concentration of the test compound was allowed to equilibrate with the tissue for 5 minutes before a concentration increment (ten-fold) was made. In each tissue the test compound was compared with theophylline as standard. Compound In Vitro Activity Theophylline 1 8-Cyclopropyl-3-ethyl-6-ethylamino-3H-purine 43.7 6-Ethylamino-3-hexyl-3H-purine -25.6 3-Benzyl-6-ethylamino-3H-purine 18.5 EXAMPLE 17 IN-VIVO STUDIES (i) The effect of test compounds in a model of bron¬ chial hyperresponsiveness (BHR) and cellular infiltration in the guinea pig induced by ovalbumin (see, for example Morley et al, Agents and Actions, Supplement, 1988, 23., 187) were studied. The test compound was administered at doses of 0.5 and 1.0 mg/kg/day given subcutaneously over 7 days by osmotic mini-pump. Theophylline and salbutamol at concen¬ trations of 1 mg/kg/day were used as standards. Dose re- sponse curves to hista ine (1-50 μg/kg) were constructed for each animal. Figures 1-2 show the results obtained. (ii) Sensitization and Challenge procedure: Male Dunkin Hartley guine pigs (Charles River) (200-250 g) were injected i.p. with ovalbumin (OVA) (0.5 ml/animal; 20 μg OVA in Al(OH) 3 (moist gel)); this preparation produced an injectable stable suspension containing excess A1(0H) 3 . Sham animals were injected with 0.5 ml Al(0H) 3 alone. After a period of 18-21 days animals were exposed to an aerosol of OVA (100 μg/ml) for 1 hour iln an exposure chamber. (iii) Bronchoalveloar lavage: Animals were anaesthe- tized, 24 hours after aerosol exposure, with urethane (25%, w/v, 7 ml/kg, i.p.) and the trachea cannulated. Bronchoal- veolar lavage (BAL) was performed by instilling 5 ml sterile saline into the lungs via teh tracheal cannula and the fluid was immediately removed. The fluid was reinject- ed and the procedure repeated 5 times in total. This pro¬ cedure resulted in a 40-60% recovery of BAL fluid from the lungs of the guinea pig. Total cell counts were perfomed on the resultant BAL fluid using an improved Neubauer haemocytometer. Cytospin preparations were prepared using a Shandon Cytospin 2 centrifuge. Two drops of BAL fluid were added to each cytospin cup and the samples were cen- trifuged for 1 min at 1300 r.p.m. Slides were fixed in acetone and stained with haemotoxylin and carbol chromo- trope according to the method described by Lendrum (Lendrum 1944) , differential cell counts were performed on each slide by counting 200 cells at random, the cell types were classified as neutrophils, eosinophils and mononuclear cells according to standard morphological criteria. Cells were counted blind. The results are expressed as the number of neutrophils, eosinophils and mononuclear cells per ml of BAL fluid. The remaining BAL fluid was centri- fuged (10 min., 1000 g) and the resultant cells and cell free supernatants were aliquotted and frozen for later assays. Compounds were solubilized in either DMSO or saline administered intraperitoreally at a dose of 5 mg/kg one hour prior to ovalbumin challenge. The results are provided below in Table 6. While the invention has been illustrated with respect to the production and use of a particular compound, it is apparent that variations and modifications of the invention can be made without departing from the spirit or scope of the invention.

Claims: WHAT IS CLAIMED IS; I; A compound of the formula (I) wherein R 3 , R 6a and R 8 are the same or different and each repre¬ sent H or a C- t -β alkyl which is unbranched or branched and unsubstituted or substituted with OH, alkoxy, C0 2 H, =NOH, =-NOCONH 2 , or =0; C 3 _ β cycloalkyl which is unsubstituted or substituted with OH, alkoxy, C0 2 H, =NOH, =NOCONH 2 , or =0; C 4 _ 8 cycloalkylalkyl wherein the cycloalkyl portion is un¬ substituted or substituted with OH, alkoxy, C0 2 H, =NOH, =N0C0NH 2 , or =0; aryl which is unsubstituted or substituted with Cl, NH 2/ alkylamino, dialkylamino, amido, alkyl- amido; and C ι .-C 3 dialkyla ido OH, alkoxy, C=NOH, C=NOCONH 2 , Ci-C- j alkyl, phenyl or benzyl; aralkyl (C-;-,) , heterocyclyl; heterocyclylalkyl (C-.-C ; and heteroaryl; R 6b represents a H or R 6a , or together R 6b , N, and R a6 make a C 3 -C 8 ring containing from one to three nitrogen atoms, from zero to two oxygen atoms, from zero to two sulfur atoms, alkoxy, C0 2 H, C0NH 2 =NOH, =N0C0NH 2 =0; and where aryl is phenyl or naphthyl, the heterocyclyl is a 5, 6 or 7 membered ring including from one to three nitrogen atoms, and from zero to two oxygen atoms, from zero to two sulfur atoms, and can be substituted as in aryl on the carbons or nitrogens of that ring; or a pharmaceutically acceptable salt thereof provided that when R 3 is a benzyl group, R 6a is a methyl or isopropyl group and R 6b is a hydrogen atom or R 3 , R 6a and R 6b are methyl groups, R 8 is other than a hydrogen atom. 2. The compound of claim 1, wherein R 3 represents a , C- ^ u alkyl, C 3 _ 7 cycloalkyl, C 4 _ 8 cycloalkylalkyl, aryl or ar(Cj._ 4 ) alkyl group; R 6a represents a C^ alkyl, C 3 _ 7 cycloalkyl, C 4 _ 8 cycloalkylalkyl, aryl arfC-..,) alkyl group, or heterocyclyl (C-.. alkyl group; R 6b represents a hydrogen atom or a C^g alkyl, C 3 _ 7 cycloalkyl, C 4 . 8 cycloalkylalkyl, aryl or ar(C 1 _ 4 )alkyl group; or -NR 6a R 6b together forms a 5-membered or 6-membered ring, which ring optionally contains one or more additional heteroato s; and R 8 represents a hydrogen atom or a C^ alkyl, C 3 _ 7 cycloalkyl, C 4 _ 8 cycloalkylalkyl, aryl, ar^. 4 )alkyl, pyridyl or pyridyl(C^ alkyl group. 3. The compound of claim 2, wherein R 3 represents a c x _ 8 alkyl group, an arfCj. alkyl group, or a c 3 _ 7 cycloalkyl group. 4. The compound of claim 2, wherein R 6a represents a Cχ. 8 alkyl group and R 6b represents a hydrogen atom. 5. The compound of claim 2, wherein R 8 represents a hydrogen atom. 6. The compound of claim 2, wherein R 8 represents a c 3 _ 7 cycloalkyl group. 7. The compound of claim 5, wherein R 8 represents a cyclopropyl group. 8. The compound of claim 2, wherein R 8 represents a C x . a alkyl group. 9. The compound of claim 7, wherein R 8 represents an isopropyl group. 10. The compound of claim 1, which is selected from 6-ethylamino-3-hexyl-3H-purine; 3-hexyl-6-methylamino-3H- purine; 3-benzyl-6-methylamino-3H-purine; 8-cyclopropyl-6- ethylamino-3-(3-methylbutyl)-3H-purine; 8-cyclopropyl-3- 5 ethyl-6-propylamino-3H-purine; 8-cyclopropyl-3-ethyl-6- methylamino-3H-purine; 3-butyl-6-ethylamino-3H-purine; 3- butyl-8-cyclopropyl-6-ethylamino-3H-purine;6-ethylamino-3- propyl-3H-purine; 8-cyclopropyl-6-ethylamino-3-propyl-3H- purine; 8-cyclopropyl-3-cyclopropylmethyl-6-ethylamino-3H- •10 purine; 3-benzyl-6-ethylamino-3H-purine; 8-cyclopropyl-6- cyclopropylamino-3-propyl-3H-purine; 3-( (2-methyl)butyl) )- 6-(2-piperazine-l-yl)ethylamino)-3H-purine; 3-cyclohexyl- methyl-6-ethylamino-3H-purine; 3-benzyl-6-ethylamino-8-(l- methylethyl)-3H-purine;3-cyclohexylmethyl-8-cyclopropyl-6- 15 ethylamino-3H-purine; 3-cyclopropylmethyl-8-isopropyl-6- ethylamino-3H-purine;3-ethyl-8-isopropyl-6-benzylamino-3H- purine; 3-ethyl-8-isopropyl-6-ethylamino-3H-purine; 3- ethyl-8-cyclopentyl-6-benzylamino-3H-purine; 3-ethyl-8- cyclopentyl-6-ethylamino-3H-purine; 3-(4-chlorobenzyl)-6- 20 ethylamino-3-purine; 3-(4-chlorobenzyl)-6-ethylamino-3H- purine; 3-(4-chlorobenzyl)-6-ethylamino-8-isopropyl-3H- purine; 3-(4-chlorobenzyl)-6-ethylamino-8-isopropyl-3H- purine; 6-benzylamino-8-cyclopropyl-3-propyl-3H-purine; 8- cyclopropyl-6-hexylamino-3-propyl-3H-purine;8-cyclopropyl- 25 3-propyl-6-(4-pyridylmethylamino)-3H-purine;6-cyclopentyl- 8-cylopropyl-3-propyl-3H-purine; 6-butylamino-8-cyclopro- pyl-3-propyl-3H-purine; 8-cyclopropyl-6-(2-hydroxyethyl- amino)-3-propyl-3H-purine; 6-(3-cyclopentyloxy-4-methoxy- benzylamiono)-8-cyclopropyl-3-propyl-3H-purine; 6-amino-8- 30 cyclopropyl-3-propyl-3H-purine;3-ethyl-6-cyclopentylamino- 8-isopropyl-3H-purine; 6-cyclohexylamino-8-isopropyl-3- propyl-3H-purine; 6-cyclopentylamino-8-isopropyl-3-propyl- 3H-purine; 3-ethyl-6-cyclopentylamino-8-cyclopropyl-3H- purine; 3-(4-chlorobenzyl)-6-cyclopentylamino-8-cyclopro- 35 pyl-3H-purine; 6-cyclopentylamino-3-(3-cyclopentyloxy-4- methoxybenzyl)-8-isopropyl-3H-purine;3-(2-chlorobenzyl)-6- cyclopentylamino-8-isopropyl-3H-purine; 8-cyclopropyl-6- diethylamino-3-propyl-3H-purine hydrochloride; 8-cyclo- propyl-6-(3-pentylamino)-3-propyl-3H-purine hydrochloride; 6-ethylamino-8-isopropyl-3-(4-pyridylmethyl)-3H-purine; 3- ethyl-8-isopropyl-6-ethylamino-3H-purine; 3-ethyl-8-cyclo- pentyl-6-benzylamino-3H-purine; 3-ethyl-8-cyclopentyl-6- ethylamino-3H-purine; 3-cylcohexylmethyl-6-ethylamino-3H- purine; 3-cyclohexylmethyl-8-cyclopropyl-6-ethylamino-3H- purine; 8-cyclopropyl-6-ethylamino-3-(3-methylbutyl)-3H- purine; 8-cyclopropyl-3-ethyl-6-propylamino-3H-purine; 8- cyclopropyl-3-cyclopropylmethyl-6-ethylamino-3H-purine; 3- hexyl-6-methylamino-3H-purine; 3-benzyl-6-methylamino-3H- purine; 3-cyclopropylmethyl-8-isopropyl-6-ethylamino-3H- purine; 3-ethyl-8-isopropyl-6-benzylamino-3H-purine; 3- butyl-6-ethylamino-3H-purine; 3-butyl-8-cyclopropyl-6- ethylamino-3H-purine; 8-cyclopropyl-6-ethylamino-3-propyl- 3H-purine; 8-cyclopropyl-6-cyclopropylamino-3-propyl-3H- purine; 3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino- 8-isopropyl-3H-purine; 3-(4-chlorobenzyl)-6-ethylamino-3H- purine; and 3-ethyl-6-ethylamino-8-( (3-cyclopentyloxy-4- methoxy)benzyl)-3H-purine. 11. The compound of claim 1, which is selected from the group consisting of 3-(3-cyclopentyloxy-4-methoxy- benzyl)-6-ethylamino-3H-purine; 3-(4-chlorobenzyl)-6- ethylamino-8-isopropyl-3H-purine; 3-(3-cyclopentyloxy-4- methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine; 6- cyclopentyl-8-cyclopropyl-3-propyl-3H-purine, and their pharmaceutically acceptable salts. 12. The compound of claim 3, wherein R 3 represents a C-,_ 4 alkyl group. 13. The compound of claim 2, wherein R 6a represents 5 methyl or ethyl and R 6b represents a hydrogen atom. 14. The compound of claim 2, wherein R 3 represents propyl. •10 15. The compound of claim 2, wherein R 3 represents substituted and unsubstituted benzyl. 16. The compound of claim 2, wherein R 3 represents cyclopropylmethyl. 17. A compound of the formula (II): wherein R 2 is O or S; R 3 , R 6a and R 8 are the same or different and each rep¬ resent H or a Ci. f , alkyl which is unbranched or branched and unsubstituted or substituted with OH, alkoxy, C0 2 H, =NOH, =NOCONH 2 , or •=0; C 3 _ 8 cycloalkyl which is unsubstituted or substituted with OH, alkoxy, C0 2 H, =NOH, =NOCONH 2 , or =0; C 4 _ 8 cycloalkylalkyl wherein the cycloalkyl portion is un¬ substituted or substituted with OH, alkoxy, C0 2 H, =NOH, =NOCONH 2 , or =0; aryl which is unsubstituted or substituted with Cl, NH 2 , alkylamino, dialkylamino, amido, Ci-C a alkyl- amido; and C x -C 3 dialkylamido OH, alkoxy, C=NOH, C=NOCONH 2 , C-i-Cj alkyl, phenyl or benzyl; aralkyl (C-.- , heterocyclyl; heterocyclylalkyl (C x -C 4 ) ; and heteroaryl; R 6b represents a H or R 6a , or together R 6b , N, and R a6 make a C 3 -C 8 ring containing from one to three nitrogen atoms, from zero to two oxygen atoms, from zero to two sulfur atoms, alkoxy, C0 2 H, CONH 2 , =NOH, =NOCONH 2 , =0; and where aryl is phenyl or naphthyl, the heterocyclyl is a 5, 6 or 7 membered ring including from one to three nitrogen atoms, and from zero to two oxygen atoms, from zero to two sulfur atoms, and can be substituted as in aryl on the carbons or nitrogens of that ring; or a pharmaceutically acceptable salt thereof, provided that when R 3 is a benzyl group, R 6a is a methyl or isopropyl group and R 6b is a hydrogen atom or R 3 , R 6a and R 6b are methyl groups, R 8 is other than a hydrogen atom. 18. The compound of claim 17, wherein R 3 represents a Ci.g alkyl, C 3 _ 7 cycloalkyl, C 4 _ 8 cycloalkylalkyl, aryl or arfC-...)alkyl group; R 6a represents a C^g alkyl, C 3 _ 7 cyclo¬ alkyl, C 4 _ 8 cycloalkylalkyl, aryl ar C-^,)alkyl group, or 5 heterocyclyl (C x _ 4 ) alkyl group; R 6b represents a hydrogen atom or a C^ alkyl, C 3 . 7 cycloalkyl, C 4 _ 8 cycloalkylalkyl, aryl or ar(C x _ 4 ) alkyl group; or -NR 5a R 6b together forms a 5-membered or 6-membered ring, which ring optionally contains one or more additional •10 heteroatoms; and R 8 represents a hydrogen atom or a C-._ 8 alkyl, C 3 _ 7 cycloalkyl, C 4 _ 8 cycloalkylalkyl, aryl, ar(C ! _ 4 )alkyl, pyridyl or pyridyl(Ci_ 4 )alkyl group. 19. The compound of claim 18, wherein R 3 represents a 15 Ci.g alkyl group, an ar(C x _ 4 ) alkyl group, or a C 3 _ 7 cyclo¬ alkyl group. 20. The compound of claim 18, wherein R 6a represents a Ci-s alkyl group and R 6b represents a hydrogen atom. 20 21. The compound of claim 18, wherein R 8 represents a hydrogen atom. 22. The compound of claim 18, wherein R 8 represents a 25 C 3 _ 7 cycloalkyl group. 23. The compound of claim 22, wherein R 8 represents a cyclopropyl group. 30 24. The compound of claim 18, wherein R 8 represents a C 1 . β alkyl group. 25. The compound of claim 24, wherein R 8 represents an isopropyl group. 26. The compound of claim 19, wherein R 3 represents a C- . _ 4 alkyl group. 27. The compound of claim 18, wherein R 6a represents methyl or ethyl and R 6b represents a hydrogen atom. 28. The compound of claim 18, wherein R 3 represents propyl. 29. The compound of claim 18, wherein R 3 represents substituted or unsubstituted benzyl. 30. The compound of claim 18, wherein R 3 represents cyclopropyl ethyl. 31. A compound of claim 17, selected from 8-cyclo- propyl-3,7-dihydro-6(4-pyridylmethylamino)-2-thio-2H-purin- 2-one; 6-cyclopentylamino-8-cyclopropyl-3,7-dihydro-3- propyl-2-thio-2H-purin-2-one; 8-cyclopropyl-3,7-dihydro-6- (2-hydroxyethylamino)-2-thio-2H-purin-2-one; and their pharmaceutically acceptable salts. 32. A compound of the formula (III) : wherein R 3 and R 8 are the same or different and each represen H or a C x _. 8 alkyl which is unbranched or branched and un substituted or substituted with OH, alkoxy, C0 2 H, =NOH, =NOCONH 2 , or =0; C 3 _ 8 cycloalkyl which is unsubstituted o substituted with OH, alkoxy, C0 2 H, =NOH, =NOCONH 2/ or =0; C 4 8 cycloalkylalkyl wherein the cycloalkyl portion is un substituted or substituted with OH, alkoxy, C0 2 H, =N0H, =NOCONH 2 , or =0; aryl which is unsubstituted or substitute with Cl, NH 2 , alkylamino, dialkylamino, amido, Ci-C-, alkyl amido; and C- t -C--, dialkylamido OH, alkoxy, C=N0H, C=N0C0NH 2 , C j -C a alkyl, phenyl or benzyl; aralkyl (C, . -,) , heterocyclyl; heterocyclylalkyl (C-i-C ; and heteroaryl. 33. The compound of claim 32, wherein R 3 represents alkyl, C 3 _ 7 cycloalkyl, C 4 _ 8 cycloalkylalkyl, aryl o arfC-...,,)alkyl group; and R 8 represents a hydrogen atom or c^ β alkyl, C 3 . 7 cycloalkyl, C 4 . 8 cycloalkylalkyl, aryl, ar(C 1 4 )alkyl, pyridyl or pyridyl(C^)alkyl group. 34. The compound of claim 32, wherein R 3 represents Ci- a alkyl group, an ar(C 1 _ 4 ) alkyl group, or a C 3 _ cycloalkyl group. 35. The compound of claim 32, wherein R 8 represents hydrogen atom. 36. The compound of claim 32, wherein R 8 represents a c 3 -7 cycloalkyl group. 37. The compound of claim 32, wherein R 8 represents a cyclopropyl group. 38. The compound of claim 32, wherein R 8 represents a C λ . B alkyl group. 39. The compound of claim 32, wherein R 8 represents an isopropyl group. 40. The compound of claim 32, wherein R 3 represents a C x .,, alkyl group. 41. The compound of claim 32, wherein R 3 represents propyl. 42. The compound of claim 32, wherein R 3 represents unsubstituted or substituted benzyl. 43. The compound of claim 32, wherein R 3 represents cyclopropylmethyl. 44. A compound according to claim 32, selected from 3-benzyl-3,7-dihydro-8-(1-methylethyl)-2,6-dithio-lH-purin- 2,6-dione; 3-cyclohexylmethyl-8-cyclopropyl-3,7-dihydro- 2,6-dithio-lH-purin-2,6-dione; 3-(4-chlorobenzyl) -8- isopropyl-3,7-dihydro-2,6-dithio-3,7-purin-2,6-dione; 8- cyclopropyl-3-cyclopropylmethyl-3,7-dihydro-2,6-dithio-lH- purin-2,6-dione; 3-(3-cyclopentyloxy-4-methoxybenzyl)-3,7- dihydro-8-isopropyl-2,6-dithio-lH-purin-2,6-dione; 8- cyclopropyl-3,7-dihydro-l,3-diethyl-2,6-dithio-lH-purin- 2,6-dione; and their pharmaceutically acceptable salts. 45. Method of effecting selective PDE IV inhibition to a patient requiring the same, which comprises adminis¬ tering an effective amount of a compound according to claims 1-44. 46. A pharmaceutical composition comprising a compound having the chemical structure set forth in claims 1-44. 47. A method of treating a mammal suffering from a disease state selected from the group consisting of asthma, allergies, inflammation, depression, atopic diseases, rhin¬ itis, dementia and disease states associated with abnormal¬ ly high physiological levels of cytokine, comprising admin- istering to the mammal an effective amount of a compound according to claims 1-44. 48. A method of preparing the compounds of claim 1, comprising reacting a compound of formula (IV) with a compound of formula (V) : R 6 _R 6 _NH (V) in the presence or absence of a suitable reaction medium and at a temperature of from about 0°C to about 100"C. 49. The method of claim 48, wherein a solvent for the reaction is selected from the group consisting of water, alcohol, hydrocarbons, and halogenated hydrocarbons. 50. The method of claim.48, wherein compounds of formula (II) are prepared by thionation of the correspond¬ ing 6-oxo compounds. 51. The method of claim 50, wherein the thionation is carried out by treating a suspension of the 6-oxo compound in pyridine with a molar excess of phosphorus pentasulphide. 52. A method of preparing the compounds of claim 1, comprising reducing compounds of formula (II) : using a suitable reducing agent. 53. The method of claim 52, wherein the reduction is effected catalytically. 54. The method of claim 52, wherein the reduction is effected in a suitable solvent selected from an alcohol, a hydrocarbon or water. 55. The method of claim 52, wherein the reduction is effected using an alkali metal in liquid ammonia or hydra- zine in the presence of a base. 56. The method of claim 52, wherein the compounds o formula (II) are prepared from the corresponding 2,6-di thioxanthine derivatives of formula (III) : • 10 by reaction with an amine R 6a R 6b NH according to the method o claim 46. 57. The method of claim 52, wherein the compounds o formula (III) are prepared from the corresponding 2 15 thioxanthine derivative by thionation.

Inventors: CAVALLA DAVID, GEHRIG ANDDRE, HOFER PETER, WINTERGEST PETER, CAVALLA, DAVID, GEHRIG, ANDDRE, HOFER, PETER, WINTERGEST, PETER
Applicants: CAVALLA DAVID, EURO CELTIQUE SA, GEHRIG ANDDRE, HOFER PETER, WINTERGEST PETER, CAVALLA, DAVID, EURO-CELTIQUE S.A., GEHRIG, ANDDRE, HOFER, PETER, WINTERGEST, PETER
Application year: 1994
Main classification: C07D473
IPC codes: A61K31, A61P11, A61P25, A61P29, A61P43, C07D473